On March 23, 2018, FDA issued draft guidance on Evaluation of Bulk Drug Substances Nominated for Use in Compounding Under Section 503B of the FDCA. Section 503B directs FDA to develop a list of bulk drug substances for which there is a clinical need (the 503B Bulks List), and the draft guidance addresses FDA policies for developing the 503B Bulks List. It includes FDA’s interpretation of the statutory phrase “bulk drug substances for which there is a clinical need” and addresses the factors and processes by which FDA intends to evaluate and list bulk drug substances.

The draft guidance recognizes two conflicting considerations for compounding drugs. On the one hand, they can meet clinical needs not met by an FDA-approved drug product. On the other hand, they are less regulated and thus pose a higher risk to patients, such as in 2012 when contaminated injectable drug products from a compounding pharmacy caused more than 60 deaths and 750 cases of infection due to fungal meningitis. The draft guidance further notes that “[i]n general, compounding using bulk drug substances presents a greater risk than compounding using FDA-approved drug products,” the source, safety, and quality of which are better known and established. The draft guidance explains that, to limit risk to patients, the 503B Bulks List is limited to substances “for which there is a clinical need serves important public health functions.”

As explained in the draft guidance, FDA interprets the statutory phrase “bulk drug substances for which there is a clinical need” to mean that a bulk drug substance may be included on the 503B Bulk List if “(1) there is a clinical need for an outsourcing facility to compound the drug product, and (2) the drug product must be compounded using the bulk drug substance.” According to the draft guidance, neither “supply issues, such as backorders” nor costs are considered within the meaning of “clinical need.”

The draft guidance outlines a two-part analysis for evaluating whether there is a clinical need for a substance that has been nominated for placement on the 503B Bulks List. Part 1 considers whether the substance is a component of an FDA-approved drug. If it is, Part 2 will not be address and the drug will not be included on the 503B Bulks List unless there is basis to conclude that two conditions are met:

  1. “(i) an attribute of the FDA-approved drug product makes it medically unsuitable to treat certain patients for a condition that FDA has identified for evaluation, and (ii) the drug product proposed to be compounded is intended to address that attribute” and
  2. “the drug product proposed to be compounded must be produced from a bulk drug substance rather than from an FDA-approved drug product[.]”

If FDA answers “yes” to both questions, the analysis proceeds to Part 2 to determine whether there is a “clinical need” for the bulk drug substance. For this inquiry, the draft guidance outlines a “balancing test” that includes consideration of:

  1. “The physical and chemical characterization of the substance;
  2. Any safety issues raised by the use of the substance in compounding;
  3. The available evidence of effectiveness or lack of effectiveness of a drug product compounded with the substance, if any such evidence exists; and
  4. Current and historical use of the substance in compounded drug products, including information about the medical condition(s) that the substance has been used to treat and any references in peer-reviewed medical literature.”

The draft guidance explains that inclusion of a substance on 503B Bulks List will be appropriate where the factors weigh in favor of a finding a “clinical need” but not otherwise.

Readers are encouraged to read the draft guidance, also available on FDA’s website. Comments and suggestions regarding the draft guidance should be submitted to FDA by May 25, 2018.